Hepatocellular carcinoma

Hepatocellular carcinoma (HCC, also called malignant hepatoma) is the most

common type of liver cancer. Most cases of HCC are secondary to either a
viral hepatitis infection (hepatitis B or C) or cirrhosis (alcoholism being the most common
cause of liver cirrhosis).
Treatment options for HCC and prognosis are dependent on many factors but
especially on tumour size and staging. Tumour grade is also important. High-grade tumours
will have a poor prognosis, while low-grade tumors may go unnoticed for many years, as is
the case in many other organs.
HCC is a relatively uncommon cancer in the United States. In countries where
hepatitis is uncommon, most cancers of the liver are not primary HCC but metastasis (cancers
spread from elsewhere in the body such as the colon).
A. Signs and symptoms
Hepatocellular carcinoma may present with yellow skin, bloating from fluid in the
abdomen, easy bruising from blood clotting abnormalities, loss of appetite, unintentional
weight loss, abdominal pain especially in the right upper quadrant, nausea, vomiting,
or feeling tired.
B. Risk factors
The main risk factors for hepatocellular carcinoma are;

Alcoholism

Hepatitis B

Hepatitis C (25% of causes globally)

Aflatoxin

Cirrhosis of the liver

Nonalcoholic steatohepatitis (if progression to cirrhosis has occurred)

Hemochromatosis

Wilson's disease (while some theorise the risk increases, case studies are rare and
suggest the opposite where Wilson's disease actually may confer protection])

Type 2 diabetes (probably aided by obesity)

Hemophilia

The most important risk factors vary widely from country to country. In countries
where Hepatitis B is endemic, such as China, Hepatitis B is the predominant cause of
Hepatocellular Carcinoma. Whereas in countries, such as the United States, where
Hepatitis B is rare because of high vaccination rates, the major cause of HCC is
Cirrhosis (often due to alcohol abuse).

The risk of hepatocellular carcinoma in type 2 diabetics is greater (from 2.5 to 7.1 times
the non diabetic risk) depending on the duration of diabetes and treatment protocol. A
suspected contributor to this increased risk is circulating insulin concentration such that
diabetics with poor insulin control or on treatments that elevate their insulin output (both
states that contribute to a higher circulating insulin concentration) show far greater risk of
hepatocellular carcinoma than diabetics on treatments that reduce circulating insulin
concentration. On this note, some diabetics who engage in tight insulin control (by keeping it
from being elevated) show risk levels low enough to be indistinguishable from the general
population. This phenomenon is thus not isolated to diabetes mellitus type 2 since poor
insulin regulation is also found in other conditions such as metabolic syndrome (specifically,
when evidence of non alcoholic fatty liver disease or NAFLD is present) and again there is
evidence of greater risk here too. While there are claims that anabolic steroid abusers are at
greater risk (theorized to be due to insulin and IGF exacerbation), the only evidence that has
been confirmed is that anabolic steroid users are more likely to have hepatocellular adenomas
(a benign form of HCC) transform into the more dangerous hepatocellular carcinoma.
When hepatocellular adenomas grow to a size of more than 68 cm, they are considered
cancerous and thus become a risk of hepatocellular carcinoma. Although hepatocellular
carcinoma most commonly affects adults, children who are affected with biliary atresia,
infantile cholestasis, glycogen-storage diseases, and other cirrhotic diseases of the liver are
predisposed to developing hepatocellular carcinoma.

Children and adolescents are unlikely to have chronic liver disease, however, if they
suffer from congenital liver disorders, this fact increases the chance of developing
hepatocellular carcinoma.
Young adults afflicted by the rare fibrolamellar variant of hepatocellular carcinoma may
have none of the typical risk factors, i.e. cirrhosis and hepatitis.

Pathogenesis[edit]
See also: Carcinogenesis
Hepatocellular carcinoma, like any other cancer, develops when there is a mutation to the cellular
machinery that causes the cell to replicate at a higher rate and/or results in the cell
avoiding apoptosis. In particular, chronic infections of hepatitis B and/or C can aid the
development of hepatocellular carcinoma by repeatedly causing the body's own immune system
to attack the liver cells, some of which are infected by the virus, others merely bystanders.
[21]
While this constant cycle of damage followed by repair can lead to mistakes during repair
which in turn lead to carcinogenesis, this hypothesis is more applicable, at present, to hepatitis
C. Chronic hepatitis C causes HCC through the stage ofcirrhosis. In chronic hepatitis B, however,
the integration of the viral genome into infected cells can directly induce a non-cirrhotic liver to
develop HCC. Alternatively, repeated consumption of large amounts of ethanol can have a
similar effect. Besides, cirrhosis is commonly caused by alcoholism, chronic hepatitis B and
chronic hepatitis C. The toxinaflatoxin from certain Aspergillus species of fungus is a carcinogen
and aids carcinogenesis of hepatocellular cancer by building up in the liver. The combined high
prevalence of rates of aflatoxin and hepatitis B in settings like China and West Africa has led to
relatively high rates of heptatocellular carcinoma in these regions. Other viral hepatitides such
ashepatitis A have no potential to become a chronic infection and thus are not related to
hepatocellular carcinoma.

Diagnosis[edit]
Hepatocellular carcinoma (HCC) most commonly appears in a person with chronic viral hepatitis
(hepatitis B or hepatitis C, 20%) or/and with cirrhosis (about 80%). These people commonly
undergo surveillance with ultrasound (US) due to the cost-effectiveness.
Surveillance differs but the American Association of Liver Diseases recommends screening Asian
men over the age of 40, Asian women over the age of 50, people with HBV and cirrhosis, and
African and North American blacks. These people are screened with US every 6 months. AFP is
a marker that is useful if it is markedly elevated. At levels less >20 sensitivity is 41-65% and
specificity is 80-94%. However, at levels >200 sensitivity is 31, specificity is 99%. [22]
Ultrasound (US) is often the first imaging and screening modality used. On US, HCC often
appears as a small hypo-echoic lesion with poorly defined margins and coarse irregular internal
echoes. When the tumor grows, it can sometimes appear heterogeneous with fibrosis, fatty
change, and calcifications. This heterogeneity can look similar to cirrhosis and the surrounding
liver parenchyma. A systemic review found that the sensitivity was 60 percent (95% CI 44-76%)
and specificity was 97 percent (95% CI 95-98%) compared with pathologic examination of an
explanted or resected liver as the reference standard. The sensitivity increases to 79% with AFP
correlation.[23]
In people with a higher suspicion of HCC (such as rising alpha-fetoprotein and des-gamma
carboxyprothrombin levels),[24] the best method of diagnosis involves a CT scan of the abdomen
using intravenous contrast agent and three-phase scanning (before contrast administration,
immediately after contrast administration, and again after a delay) to increase the ability of
the radiologist to detect small or subtle tumors. It is important to optimize the parameters of the

CT examination, because the underlying liver disease that most people with HCC have can make
the findings more difficult to appreciate.
Triple phase helical CT improves the detection of these tumors. Due to the increased vascularity
of hepatocellular carcinoma, the classic finding on CT imaging ishypervascularity in the arterial
phase with washout in the portal and delayed phases. A pseudocapsule, a mosaic pattern and
both calcifications and intralesional fat may be appreciated. A systemic review found that the
sensitivity was 68 percent (95% CI 55-80%) and specificity was 93 percent (95% CI 89-96%)
compared with pathologic examination of an explanted or resected liver as the reference
standard. With triple phase helical CT, the sensitivity 90% or higher, but this data has not been
confirmed with autopsy studies.[23]
Classification of HCC on CT: Liver Image Reporting and Data System (LI-RADS): LI-RADs is the
new way to standardize/classify the HCC lesions found on CT and MRI. Radiologists use this
classification system in their imaging reports in order to further characterize suspicious lesions.
As a general introduction, LR1 and LR2 get continued surveillance. LR3 has variable follow up.
LR4 gets close follow up, additional imaging or treatment. LR5 gets treatment. [25]
On CT, HCC can have three distinct patterns of growth:

A single large tumor

Multiple tumors

Poorly defined tumor with an infiltrative growth pattern

A biopsy is not needed to confirm the diagnosis of HCC if certain imaging criteria are met.
CT scans use contrast agents, which are typically iodine- or barium-based. Some patients are
allergic to one or both of these contrast agents, most often iodine. Usually the allergic reaction is
manageable and not life-threatening.
An alternative to a CT imaging study would be Magnetic Resonance Imaging (MRI). MRI has
about the same sensitivity for detecting HCC has helical CT. However, MRI has the advantage of
delivering high resolution images of the liver without nephrotoxic contrast agents or ionizing
radiation. HCC appears as a high intensity pattern on T2 weighted images and a low intensity
pattern on T1 weighted images. The advantage of MRI is that is has improved sensitivity and
specificity when compared to US and CT in cirrhotic patients in whom it can be difficult to
differentiate HCC from regenerative nodules. A systematic review found that the sensitivity was
81 percent (95% CI 70-91%) and specificity was 85 percent (95% CI 77-93%) compared with
pathologic examination of an explanted or resected liver as the reference standard. [23] The
sensitivity is further increased gadoxetic acid-enhanced and diffusion-weighted imaging are
combined. Despite the advantages of MRI, helical CT remains the technique of choice among
radiologists due to the high cost and long image acquisition time of MRI.
In a review article of the screening, diagnosis and treatment of hepatocellular carcinoma, 4
articles were selected for comparing the accuracy of CT and MRI in diagnosing thismalignancy.
[26]
Radiographic diagnosis was verified against post-transplantation biopsy as the gold standard.
With the exception of one instance of specificity, it was discovered that MRI was
more sensitive and specific than CT in all four studies.

Pathology[edit]

Micrograph of hepatocellular carcinoma. Liver biopsy. Trichrome stain.

Macroscopically, liver cancer appears as a nodular or infiltrative tumor. The nodular type may be
solitary (large mass) or multiple (when developed as a complication of cirrhosis). Tumor nodules
are round to oval, grey or green (if the tumor produces bile), well circumscribed but not
encapsulated. The diffuse type is poorly circumscribed and infiltrates the portal veins, or the
hepatic veins (rarely).
Microscopically, there are four architectural and cytological types (patterns) of hepatocellular
carcinoma: fibrolamellar, pseudoglandular(adenoid), pleomorphic (giant cell) and clear cell. In
well differentiated forms, tumor cells resemble hepatocytes, form trabeculae, cords and nests,
and may contain bile pigment in cytoplasm. In poorly differentiated forms, malignant epithelial
cells are discohesive,pleomorphic, anaplastic, giant. The tumor has a scant stroma and central
necrosis because of the poor vascularization.[27]

Staging[edit]
Important features that guide treatment include:

size

spread (stage)

involvement of liver vessels

presence of a tumor capsule

presence of extrahepatic metastases

presence of daughter nodules

vascularity of the tumor

MRI is the best imaging method to detect the presence of a tumor capsule.

Prevention[edit]

Since hepatitis B or C is one of the main causes of hepatocellular carcinoma, prevention of this
infection is key to then prevent hepatocellular carcinoma. Thus,
childhoodvaccination against hepatitis B may reduce the risk of liver cancer in the future. [28]
In the case of patients with cirrhosis, alcohol consumption is to be avoided. Also, screening
for hemochromatosis may be beneficial for some patients.[29]
It is unclear if screening those with chronic liver disease for hepatocellular carcinoma improves
outcomes.[30]

Management[edit]
This article's factual accuracy may be compromised due to out-of-date
information. Please update this article to reflect recent events or newly available
information. (January 2010)

Liver transplantation to replace the diseased liver with a cadaveric liver or a living donor
graft has historically low survival rates (20%-36%). During 19962001 the rate had improved
to 61.1%, likely related to adoption of the Milan criteria at US transplantation centers.
Expanded Shanghai criteria in China resulted in overall survival and disease-free survival
rates similar to the Milan criteria.[31] Studies from the late 2000 obtained higher survival rates
ranging from 67% to 91%.[32] If the liver tumor has metastasized, the immuno-suppressant
post-transplant drugs decrease the chance of survival. Considering this objective risk in
conjunction with the potentially high rate of survival, some recent studies conclude that: "LTx
can be a curative approach for patients with advanced HCC without extrahepatic
metastasis".[33] For those reasons, and others, it is considered nowadays that patient
selection is a major key for success.[34]

A receptor tyrosine kinase inhibitor, Sorafenib, approved by the US FDA in December

2005 and in Europe in July 2006, may be used in patients with advanced hepatocellular
carcinoma.[35] Sorafenib is a small molecule that inhibits tumor-cell proliferation and tumor
angionesis. It has been shown in a Spanish phase III clinical trial to add two months to the
lifespan of late stage HCC patients with well preserved liver function. [36] It also increases the
rate of apoptosis in other tumor models. The results indicated that single-agent sorafenib
might have a beneficial therapeutic effect. In this study, for instance, the median overall
survival was of 9.2 months and the median time to progression was of 5.5 months. Also, the
survival benefit represented a 31% relative reduction in the risk of death. [37]

Surgical resection to remove a tumor together with surrounding liver tissue while
preserving enough liver remnant for normal body function. This treatment offers the best
prognosis for long-term survival, but only 10-15% of patients are suitable for surgical
resection. This is often because of extensive disease or poor liver function. Resection in
cirrhotic patients carries high morbidity and mortality. The expected liver remnant should be
more than 25% of the total size for a non-cirrhotic liver, while that should be more than 40%
of the total size for a cirrhotic liver. The overall recurrence rate after resection is 50-60%. The
Singapore Liver Cancer Recurrence (SLICER) score can be used to estimate risk of
recurrence after surgery.[38]

Interventional Radiology (IR) Procedures and Management

Transcatheter arterial chemoembolization (TACE) is usually performed for unresectable

tumors or as a temporary treatment while waiting for liver transplant. TACE is done by
injecting an antineoplastic drug (e.g. cisplatin) mixed with a radioopaque contrast (e.g.
Lipiodol) and an embolic agent (e.g. Gelfoam) into the right or left hepatic artery via the groin
artery. The goal of the procedure it to restrict the tumors vascular supply while supplying a
targeted chemotherapeutic agent. TACE has been shown to increase survival and to
downstage HCC in patients who exceed the Milan criteria for liver transplant. Patients who

undergo the procedure may are followed with CT scans and may need additional TACE
procedures if the tumor persists.[39] As of 2005, multiple trials show objective tumor responses
and slowed tumor progression but questionable survival benefit compared to supportive
care; greatest benefit seen in patients with preserved liver function, absence of vascular
invasion, and smallest tumors. TACE is not suitable for big tumors (>8 cm), presence of
portal vein thrombus, tumors with portal-systemic shunt and patients with poor liver function.

Gross anatomy of hepatocellular carcinoma

Radiofrequency ablation (RFA) uses high frequency radio-waves to destroy tumor by

local heating. The electrodes are inserted into the liver tumor under ultrasound image
guidance using percutaneous, laparoscopic or open surgical approach. It is suitable for small
tumors (<5 cm). RFA has the best outcomes in patients with a solitary tumor less than 4 mm.
[40]
Since it is a local treatment and has minimal affect on normal healthy tissue, it can be
repeated multiple times. Survival is better for those with smaller tumors. In one study, In one
series of 302 patients, the three-year survival rates for lesions >5 cm, 2.1 to 5 cm, and 2 cm
were 59, 74, and 91 percent, respectively.[41] A large randomised trial comparing surgical
resection and RFA for small HCC showed similar 4 years-survival and less morbidities for
patients treated with RFA.[42]

Selective internal radiation therapy (SIRT) can be used to destroy the tumor from within
(thus minimizing exposure to healthy tissue). Similar to TACE, this is a procedure in which an
interventional radiologist selectively injects the artery or arteries supplying the tumor with a
chemotherapeutic agent. The agent is typically Yttrium-90 (Y-90) incorporated into embolic
microspheres that lodge in the tumor vasculature causing ischemia and delivering their
radiation dose directly to the lesion. This technique allows for a higher, local dose of radiation
to be delivered directly to the tumor while sparing normal healthy tissue. While not curative,
patients have increased survival. No studies have been done to compare whether SIRT is
superior to TACE in terms of survival outcomes, although retrospective studies suggest
similar efficacy.[43] There are currently two products available, SIRSpheres and TheraSphere The latter is an FDA approved treatment for primary liver cancer
(HCC) which has been shown in clinical trials to increase survival rate of low-risk patients.
SIR-Spheres are FDA approved for the treatment of metastatic colorectal cancer but outside
the US SIR-Spheres are approved for the treatment of any non-resectable liver cancer
including primary liver cancer.

Intra-arterial iodine-131lipiodol administration Efficacy demonstrated in unresectable

patients, those with portal vein thrombus. This treatment is also used as adjuvant therapy in
resected patients (Lau at et, 1999). It is believed to raise the 3-year survival rate from 46 to
86%. This adjuvant therapy is in phase III clinical trials in Singapore and is available as a
standard medical treatment to qualified patients in Hong Kong.

Percutaneous ethanol injection (PEI) well tolerated, high RR in small (<3 cm) solitary
tumors; as of 2005, no randomized trial comparing resection to percutaneous treatments;
recurrence rates similar to those for postresection. However a comparative study found that
local therapy can achieve a 5-year survival rate of around 60% for patients with small HCC. [44]

Combined PEI and TACE can be used for tumors larger than 4 cm in diameter, although
some Italian groups have had success with larger tumours using TACE alone.

Portal Vein Embolization (PVE): Using a percutaneous transhepatic approach, an

interventional radiologist embolizes the portal vein supplying the side of the liver with the
tumor. Compensatory hypertrophy of the surviving lobe can qualify the patient for resection.
This procedure can also serve as a bridge to transplant.[45]

Complications: The most common complication of both TACE and SIRT is post embolization
syndrome occurring in 60-80% of patients in TACE and 20-55% in SIRT.[46] Typical findings of post
embolization syndrome are fatigue, constitutional symptoms and abdominal pain. It usually lasts
34 days with full resolution in 710 days. Other more serious complications from TACE and
SIRT include liver failure, hepatic dysfunction and gastric ulceration from non-target embolization
of the left gastric. Less than 1% of patients who undergo SIRT develop radiation pneumonitis.
Complications of RFA are rare but include abscess formation, subcapsular hematoma and tract
seeding.
While surgical resection offers the best chance at a cure for hepatocellular carcinoma, the tumors
are often inoperable due to large size or spread into vascular and adjacent structures. Medical
management is generally palliative and aimed at reducing liver disease symptoms.
Chemotherapy is traditionally ineffective. Interventional radiology offers minimally invasive
treatments that can improve quality of life, increase survival, and reduce symptoms in these
patients.
Other Management

High intensity focused ultrasound (HIFU) (not to be confused with normal diagnostic
ultrasound) is a new technique which uses much more powerful ultrasound to treat the
tumour. Still at a very experimental stage. Most of the work has been done in China. Some
early work is being done in Oxford and London in the UK.

Hormonal therapy Antiestrogen therapy with tamoxifen studied in several trials, mixed
results across studies, but generally considered ineffective Octreotide (somatostatin
analogue) showed 13-month MS v 4-month MS in untreated patients in a small randomized
study; results not reproduced.

Adjuvant chemotherapy: No randomized trials showing benefit of neoadjuvant or adjuvant

systemic therapy in HCC; single trial showed decrease in new tumors in patients receiving
oral synthetic retinoid for 12 months after resection/ablation; results not reproduced. Clinical
trials have varying results.[47]

Palliative: Regimens that

included doxorubicin, cisplatin, fluorouracil, interferon, epirubicin, or taxol, as single agents or
in combination, have not shown any survival benefit (RR, 0%-25%); a few isolated major
responses allowed patients to undergo partial hepatectomy; no published results from any
randomized trial of systemic chemotherapy.

Cryosurgery: Cryosurgery is a new technique that can destroy tumors in a variety of sites
(brain, breast, kidney, prostate, liver). Cryosurgery is the destruction of abnormal tissue using
sub-zero temperatures. The tumor is not removed and the destroyed cancer is left to be
reabsorbed by the body. Initial results in properly selected patients with unresectable liver
tumors are equivalent to those of resection. Cryosurgery involves the placement of a
stainless steel probe into the center of the tumor. Liquid nitrogen is circulated through the
end of this device. The tumor and a half inch margin of normal liver are frozen to -190 C for
15 minutes, which is lethal to all tissues. The area is thawed for 10 minutes and then refrozen to -190 C for another 15 minutes. After the tumor has thawed, the probe is removed,
bleeding is controlled, and the procedure is complete. The patient will spend the first post-

operative night in the intensive care unit and typically is discharged in 3 5 days. Proper
selection of patients and attention to detail in performing the cryosurgical procedure are
mandatory in order to achieve good results and outcomes. Frequently, cryosurgery is used in
conjunction with liver resection as some of the tumors are removed while others are treated
with cryosurgery. Patients may also have insertion of a hepatic intra-arterial catheter for postoperative chemotherapy. As with liver resection, the surgeon should have experience with
cryosurgical techniques in order to provide the best treatment possible.

Interventional radiology
A systematic review assessed 12 articles involving a total of 318 patients with
hepatocellular carcinoma treated with Yttrium-90 radioembolization.[48] Excluding a study of
only one patient, post-treatment CT evaluation of the tumor showed a response ranging from
29 to 100% of patients evaluated, with all but two studies showing a response of 71% or
greater.

Prognosis[edit]
The usual outcome is poor, because only 1020% of hepatocellular carcinomas can be removed
completely using surgery. If the cancer cannot be completely removed, the disease is usually
deadly within 3 to 6 months.[49] This is partially due to late presentation with large tumours, but
also the lack of medical expertise and facilities in the regions with high HCC prevalence.
However, survival can vary, and occasionally people will survive much longer than 6 months. The
prognosis for metastatic or unresectable hepatocellular carcinoma has recently improved due to
the approval of sorafenib (Nexavar) for advanced hepatocellular carcinoma.

Epidemiology[edit]

Age-standardized death from liver cancer per 100,000 inhabitants in 2004.[50]

no data
less than 7.5
7.5-15
15-22.5
22.5-30
30-37.5
37.5-45
45-52.5
52.5-60
60-67.5
67.5-75
75-110
more than 110

HCC is one of the most common tumors worldwide. The epidemiology of HCC exhibits two main
patterns, one in North America andWestern Europe and another in non-Western countries, such

as those in sub-Saharan Africa, central and Southeast Asia, and the Amazon basin. Males are
affected more than females usually and it is most common between the age of 30 to 50,
[1]
Hepatocellular carcinoma causes 662,000 deaths worldwide per year [51] about half of them
in China.

Africa and Asia[edit]

In some parts of the world, such as sub-Saharan Africa and Southeast Asia, HCC is the most
common cancer, generally affecting men more than women, and with an age of onset between
late teens and 30s. This variability is in part due to the different patterns of hepatitis
B and hepatitis C transmission in different populations - infection at or around birth predispose to
earlier cancers than if people are infected later. The time between hepatitis B infection and
development into HCC can be years, even decades, but from diagnosis of HCC to death the
average survival period is only 5.9 months according to one Chinese study during the 1970-80s,
or 3 months (mediansurvival time) in Sub-Saharan Africa according to Manson's textbook of
tropical diseases. HCC is one of the deadliest cancers in Chinawhere chronic hepatitis B is found
in 90% of cases. In Japan, chronic hepatitis C is associated with 90% of HCC cases. Food
infected withAspergillus flavus (especially peanuts and corns stored during prolonged wet
seasons) which produces aflatoxin poses another risk factor for HCC.

North America and Western Europe[edit]

Most malignant tumors of the liver discovered in Western patients are metastases (spread) from
tumors elsewhere.[1] In the West, HCC is generally seen as a rare cancer, normally of those with
pre-existing liver disease. It is often detected by ultrasound screening, and so can be discovered
by health-care facilities much earlier than in developing regions such as Sub-Saharan Africa.
Acute and chronic hepatic porphyrias (acute intermittent porphyria, porphyria cutanea
tarda, hereditary coproporphyria, variegate porphyria) and tyrosinemia type I are risk factors for
hepatocellular carcinoma. The diagnosis of an acute hepatic porphyria (AIP, HCP, VP) should be
sought in patients with hepatocellular carcinoma without typical risk factors of hepatitis B or C,
alcoholic liver cirrhosis or hemochromatosis. Both active and latent genetic carriers of acute
hepatic porphyrias are at risk for this cancer, although latent genetic carriers have developed the
cancer at a later age than those with classic symptoms. Patients with acute hepatic porphyrias
should be monitored for hepatocellular carcinoma.

Research[edit]
Pre-clinical[edit]
Current research includes the search for the genes that are disregulated in HCC,
[52]
protein markers,[53] non-coding RNAs (such as TUC338)[54] and other predictive biomarkers.[55]
[56]
As similar research is yielding results in various other malignant diseases, it is hoped that
identifying the aberrant genes and the resultant proteins could lead to the identification of
pharmacological interventions for HCC.[57]

Clinical[edit]
JX-594, an oncolytic virus, has orphan drug designation for this condition and is undergoing
clinical trials.[58]
Hepcortespenlisimut-L, an oral cancer vaccine also has US FDA orphan drug designation for
hepatocellular carcinoma.[59]